ABSTRACT Recent developments in real-time functional magnetic resonance imaging (rt-fMRI) enable novel behavioral therapies for addiction and the simultaneous imaging of the brain's response to treatment. With rt-fMRI, the therapeutic process can become multi-modal and adaptive, wherein a cognitive behavioral intervention itself can co-evolve with a responding brain. In a manner that has never before been possible, self-control can be guided by signals from one's own neural activity. Toward this end, the broad goals of our proposal are threefold. First, we will expand, evaluate, and refine the capabilities of our existing rt-fMRI system (LaConte et al., 2007 - Appendix A). Second, given the profound differential roles of cue-induced craving and cognitive control on the initiation, maintenance, and cessation of substance abuse, we apply rt-fMRI to decrease neural activations associated with craving and increase neural activations associated with cognitive control. Third, we will assess the feasibility and effectiveness of implementing rt-fMRI neurofeedback to aid in maintaining abstinence in treatment-seeking substance users. Thus, the overarching goal of our application is to use neurobehavioral states associated with craving and cognitive control to develop an optimal neurofeedback signal that can be efficiently modulated by substance abusers to facilitate self-control. We expect that achieving the aims of this application will lead to technical and therapeutic innovations to be further pursued in subsequent full-scale studies. The Specific Aims for the R21 phase (years 1 and 2) will provide an assessment of the relative advantages of localized and distributed rt-fMRI methods and quantitative results on how well individuals can modulate fMRI-computer interfaces using cognitive control and craving alleviation strategies. Thus we aim to: 1. Expand and refine the capabilities of our existing real-time fMRI feedback system. 2. Modulate neural signals of cue-induced craving and cognitive control in the real-time environment. The Specific Aims for the R33 phase (years 3, 4, 5) will provide critical experimental controls to the R21 findings and will explore methods to combine distributed and localized approaches to rt-fMRI. We will also assess the feasibility of using fMRI-based neurofeedback to facilitate smoking cessation in treatment-seeking smokers, obtaining hypothesis-generating data for future large-scale studies. Thus we aim to: 3. Improve neurofeedback signals and validate these signals using control tasks. 4. Pilot the feasibility and effectiveness of implementing neurofeedback in treatment-seeking smokers.